Abstract

Background

Transcranial Direct Current Stimulation (tDCS) is an emerging approach for improving capacity in activities of daily living (ADL) and upper limb function after stroke. However, it remains unclear what type of tDCS stimulation is most effective. Our aim was to give an overview of the evidence network regarding the efficacy and safety of tDCS and to estimate the effectiveness of the different stimulation types.

Methods

We performed a systematic review of randomised trials using network meta-analysis (NMA), searching the following databases until 5 July 2016: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, and four other databases. We included studies with adult people with stroke. We compared any kind of active tDCS (anodal, cathodal, or dual, that is applying anodal and cathodal tDCS concurrently) regarding improvement of our primary outcome of ADL capacity, versus control, after stroke. PROSPERO ID: CRD42016042055.

Results

We included 26 studies with 754 participants. Our NMA showed evidence of an effect of cathodal tDCS in improving our primary outcome, that of ADL capacity (standardized mean difference, SMD = 0.42; 95% CI 0.14 to 0.70). tDCS did not improve our secondary outcome, that of arm function, measured by the Fugl-Meyer upper extremity assessment (FM-UE). There was no difference in safety between tDCS and its control interventions, measured by the number of dropouts and adverse events.

Conclusion

Comparing different forms of tDCS shows that cathodal tDCS is the most promising treatment option to improve ADL capacity in people with stroke.

tDCS is relatively inexpensive, easy to administer and portable, hence constituting an ideal adjuvant therapy during stroke rehabilitation. It works by applying a weak and constant direct current to the brain and has the ability to either enhance or suppress cortical excitability, with effect lasting up to several hours after the stimulation [7, 8, 9]. Hypothetically, this technique makes tDCS a potentially useful tool to modulate neuronal inhibitory and excitatory networks of the affected and the non-affected hemisphere post stroke to enhance, for example, upper limb motor recovery [10, 11]. Three different stimulation types can be distinguished.

In anodal stimulation, the anodal electrode (+) usually is placed over the lesioned brain area and the reference electrode over the contralateral orbit [12]. This leads to subthreshold depolarization, hence promoting neural excitation [3].

In cathodal stimulation, the cathode (−) usually is placed over the non-lesioned brain area and the reference electrode over the contralateral orbit [12], leading to subthreshold polarization and hence inhibiting neural activity [3].

However, the literature does not provide clear guidelines, not only regarding the tDCS type, but also regarding the electrode configuration [14], the amount of current applied and the duration of tDCS, or the question if tDCS should be applied as a standalone therapy or in combination with other treatments, like robot-assisted therapy [15].

Rationale

There is so far conflicting evidence from systematic reviews of randomised controlled trials on the effectiveness of different tDCS approaches after stroke. For example, over the past two decades more than 30 randomised clinical trials have investigated the effects of different tDCS stimulation techniques for stroke, and there are 55 ongoing trials [16]. However, the resulting network of evidence from randomised controlled trials (RCTs) investigating different types of tDCS (i.e., anodal, cathodal or dual) as well as their comparators like sham tDCS, physical rehabilitation or pharmacological agents has not yet been analyzed in a systematic review so far.

A network meta-analysis (NMA), also known as multiple treatment comparison meta-analysis or mixed treatment comparison analysis, allows for a quantitative synthesis of the evidence network. This is made possible by combining direct evidence from head-to-head comparisons of three or more interventions within randomised trials with indirect evidence across randomised trials on the basis of a common comparator [17, 18, 19, 20]. Network meta-analysis has many advantages over traditional pairwise meta-analysis, such as visualizing and facilitating the interpretation of the wider picture of the evidence and improving understanding of the relative merits of these different types of neuromodulation when compared to sham tDCS and/or another comparator such as exercise therapy and/or pharmacological agents [21, 22]. By borrowing strength from indirect evidence to gain certainty about all treatment comparisons, network meta-analysis allows comparative effects that have not been investigated directly in randomised clinical trials to be estimated and ranked [22, 23].

Objective

The aim of our systematic review with NMA was to give an overview of the evidence network of randomised controlled trials of tDCS (anodal, cathodal, or dual) for improving capacity in activities of daily living (ADL) and upper limb function after stroke, as well as its safety, and to estimate and rank the relative effectiveness of the different stimulation types, while taking into account potentially important treatment effect modifiers.

Objective: The aim of this study was to identify the effects of home-based VR-based motor rehabilitation on (1) cortical reorganization, (2) corticospinal tract, and (3) functional recovery after stroke in comparison to home-based occupational therapy.

Methods: We conducted a parallel-group, controlled trial to compare the effectiveness of domiciliary VR-based therapy with occupational therapy in inducing motor recovery of the upper extremities. A total of 35 participants with chronic stroke underwent 3 weeks of home-based treatment. A group of subjects was trained using a VR-based system for motor rehabilitation, while the control group followed a conventional therapy. Motor function was evaluated at baseline, after the intervention, and at 12-weeks follow-up. In a subgroup of subjects, we used Navigated Brain Stimulation (NBS) procedures to measure the effect of the interventions on corticospinal excitability and cortical reorganization.

Results: Results from the system’s recordings and clinical evaluation showed significantly greater functional recovery for the experimental group when compared with the control group (1.53, SD 2.4 in Chedoke Arm and Hand Activity Inventory). However, functional improvements did not reach clinical significance. After the therapy, physiological measures obtained from a subgroup of subjects revealed an increased corticospinal excitability for distal muscles driven by the pathological hemisphere, that is, abductor pollicis brevis. We also observed a displacement of the centroid of the cortical map for each tested muscle in the damaged hemisphere, which strongly correlated with improvements in clinical scales.

Introduction

After initial hospitalization, many stroke patients return home relatively soon despite still suffering from impairments that require continuous rehabilitation [1]. Therefore, ¼ to ¾ of patients display persistent functional limitations for a period of 3 to 6 months after stroke [2]. Although clinicians may prescribe a home exercise regimen, reports indicate that only one-third of patients actually accomplish it [3]. Consequently, substantial gains in health-related quality of life during inpatient stroke rehabilitation may be followed by equally substantial declines in the 6 months after discharge [4]. Multiple studies have shown, however, that supported discharge combined with at home rehabilitation services does not compromise clinical inpatient outcomes [5–7] and may enhance recovery in subacute stroke patients [8]. Hence, it is essential that new approaches are deployed that help to manage chronic conditions associated with stroke, including domiciliary interventions [9] and the augmentation of current rehabilitation approaches in order to enhance their efficiency. There should be increased provision of home-based rehabilitation services for community-based adults following stroke, taking cost-effectiveness, and a quick family and social reintegration into account [10].

One of the latest approaches in rehabilitation science is based on the use of robotics and virtual reality (VR), which allow remote delivery of customized treatment by combining dedicated interface devices with automatized training scenarios [10–12]. Several studies have tested the acceptability of VR-based setups as an intervention and evaluation tool for rehabilitation [13–15]. One example of this technology is the, so called, Rehabilitation Gaming System (RGS) [16], which has been shown to be effective in the rehabilitation of the upper extremities in the acute and the chronic phases of stroke [13]. However, so far little work exists on the quantitative assessment of the clinical impact of VR based approaches and their effects on neural reorganization that can directly inform the design of these systems and their application in the domiciliary context. The main objective of this paper is to further explore the potential and limitations of VR technologies in domiciliary settings. Specifically, we examine the efficacy of a VR-based therapy when used at home for (1) assessing functional improvement, (2) facilitating functional recovery of the upper-limbs, and (3) inducing cortical reorganization. This is the first study testing the effects of VR-based therapy on cortical reorganization and corticospinal integrity using NBS.

Methods

Design

We conducted a parallel-group, controlled trial in order to compare the effectiveness of domiciliary VR-based therapy versus domiciliary occupational therapy (OT) in inducing functional recovery and cortical reorganization in chronic stroke patients.

Participants

Participants were first approached by an occupational therapist from the rehabilitation units of Hospital Esperanza and Hospital Vall d’Hebron from Barcelona to determine their interest in participating in a research project. Recruited participants met the following inclusion criteria: (1) mild-to-moderate upper-limbs hemiparesis (Proximal MRC>2) secondary to a first-ever stroke (>12 months post-stroke), (2) age between 45 and 85 years old, (3) absence of any major cognitive impairment (Mini-Mental State Evaluation, MMSE>22), and (4) previous experience with RGS in the clinic. The ethics committee of clinical research of the Parc de Salut Mar and Vall d’Hebron Research Institute approved the experimental guidelines. Thirty-nine participants at the chronic stage post-stroke were recruited for the study by two occupational therapists, between October 2011 and January 2012, and were assigned to a RGS (n=20) or a control group (n=19) using stratified permuted block randomization methods for balancing the participants’ demographics and clinical scores at baseline (Table 1). One participant in the RGS group refused to participate. Prior to the experiment, participants signed informed consent forms. This trial was not registered at or before the onset of participants’ enrollment because it is a pilot study that evaluates the feasibility of a prototype device. However, this study was registered retrospectively in ClinicalTrials.gov and has the identifier NCT02699398.

Instrumentation

Description of the Rehabilitation Gaming System

The RGS integrates a paradigm of goal-directed action execution and motor imagery [17], allowing the user to control a virtual body (avatar) through an image capture device (Figure 1). For this study, we developed training and evaluation scenarios within the RGS framework. In the Spheroids training scenario (Figure 1), the user has to perform bilateral reaching movements to intercept and grasp a maximum number of spheres moving towards him [16]. RGS captures only joint flexion and extension and filters out the participant’s trunk movements, therefore preventing the execution of compensatory body movements [18]. This task was defined by three difficulty parameters, each of them associated with a specific performance descriptor: (1) different trajectories of the spheres require different ranges of joint motion for elbow and shoulder, (2) the size of the spheres require different hand and grasp precision and perceptual abilities, and (3) the velocity of the spheres require different movement speeds and timing. All these parameters, also including the range of finger flexion and extension required to grasp and release spheroids, were dynamically modulated by the RGS Adaptive Difficulty Controller [19] to maintain the performance ratio (ie, successful trials over the total trials) above 0.6 and below 0.8, optimizing effort and reinforcement during training [20]. […]

Figure 1. Experimental setup and protocol: (A) Movements of the user’s upper limbs are captured and mapped onto an avatar displayed on a screen in first person perspective so that the user sees the movements of the virtual upper extremities. A pair of data gloves equipped with bend sensors captures finger flexion. (B) The Spheroids is divided into three subtasks: hit, grasp, and place. A white separator line divides the workspace in a paretic and non-paretic zone only allowing for ipsilateral movements.(C) The experimental protocol. Evaluation periods (Eval.) indicate clinical evaluations using standard clinical scales and Navigated Brain Stimulation procedures (NBS). These evaluations took place before the first session (W0), after the last session of the treatment (day 15, W3), and at follow-up (week 12, W12).

Abstract

Background

Upper limb paresis is one of the most frequent and persistent impairments following stroke. Only 12–34% of stroke patients achieve full recovery of upper limb functioning, which seems to be required to habitually use the affected arm in daily tasks. Although the recovery of upper limb functioning is most pronounced during the first 4 weeks post stroke, there are few studies investigating the effect of rehabilitation during this critical time window. The purpose of this trial is to determine the effect of electrical somatosensory stimulation (ESS) initiated in the acute stroke phase on the recovery of upper limb functioning in a nonselected sample of stroke patients.

Methods/design

A sample of 102 patients with upper limb paresis of varying degrees of severity is assigned to either the intervention or the control group using stratified random sampling. The intervention group receives ESS plus usual rehabilitation and the control group receives sham ESS plus usual rehabilitation. The intervention is applied as 1 h of ESS/sham ESS daily, followed by motor training of the affected upper limb. The ESS/sham ESS treatment is initiated within 7 days from stroke onset and it is delivered during hospitalization, but no longer than 4 weeks post stroke. The primary outcome is hand dexterity assessed by the Box and Block Test; secondary outcomes are the Fugl-Meyer Assessment, hand grip strength, pinch strength, perceptual threshold of touch, degree of pain, and modified Rankin Scale score. Outcome measurements are conducted at baseline, post intervention and at 6-month follow-up.

Discussion

Because of the wide inclusion criteria, we believe that the results can be generalized to the larger population of patients with a first-ever stroke who present with an upper limb paresis of varying severity. On the other hand, the sample size (n = 102) may preclude subgroup analyses in such a heterogeneous sample. The sham ESS treatment totals a mere 2% of the active ESS treatment delivered to the intervention group per ESS session, and we consider that this dose is too small to induce a treatment effect.

Background

Stroke is ranked as the third largest cause of disease burden globally [1], causing substantial physical, psychological and financial demands on patients, families, and societies at large [2, 3, 4]. Upper limb paresis is one of the most frequent impairments following stroke and affects 48–77% of patients in the acute stroke phase [5, 6, 7]. Moreover, upper limb paresis has been identified as a major obstacle to regaining independence in activities of daily living (ADLs) [8]. In fact, only 12–34% of the patients achieve full functional recovery of the affected upper limb at 6 months post stroke [9, 10]. This represents a considerable challenge since near complete functional recovery is required to routinely involve the affected upper limb in performing ADLs [11].

Recovery of upper limb functioning is typically pronounced during the first month and subsequently levels off by 6 months post stroke [12, 13, 14]. Regaining hand dexterity (i.e., motor skills such as reaching, grasping, gripping, moving and releasing objects) is often achieved already within the first 4 weeks, implying that there may be a critical time window for recovery of upper limb functioning [9, 10] during which rehabilitation efforts may maximize functional recovery. However, there are few studies investigating the effect of motor rehabilitation methods in the initial weeks after stroke.

Electrical stimulation (ES) is one of the methods that have been used to facilitate recovery of upper limb functioning following stroke. ES can induce a muscle contraction, or it can be a somatosensory stimulation below the motor threshold [15]. The majority of studies using ES have been conducted in chronic stroke and, therefore, it remains unknown to what extent ES applied in the acute phase after stroke could affect the recovery of upper limb functioning. Also, these investigations have largely focused on ES that induces muscle contraction. In healthy persons, the application of low-intensity ES with no or small motor responses to peripheral hand nerves [16, 17, 18, 19, 20], forearm muscles [21] or the whole hand [22, 23] elicits an increase in the cortical excitability of the representations that control the stimulated body parts, which seems to outlast the stimulation period itself [18, 21, 23]. It has been hypothesized that increasing the amount of somatosensory input may enhance the motor recovery of patients following stroke [24]. Recent data on acute, subacute and mostly chronic stroke patients suggest that a single 2-h session of ESS to the peripheral hand nerves leads to transient improvement of pinch force, movement kinematics and upper limb motor skills required for ADL performance [25, 26, 27, 28, 29, 30, 31]. However, ESS was only used in conjunction with motor training in one of these studies [29]. Interestingly, there is some evidence that multiple sessions of ESS to the peripheral hand nerves, in conjunction with motor training, might improve motor skills of the paretic upper limb in subacute [32, 33] and chronic stroke patients [34], and, moreover, that these positive results seems to be long lasting [34]. However, the effect of ESS in conjunction with motor training has never been investigated in acute stroke patients. It is noteworthy that ESS is benign in nature, causes patients minimal discomfort and adverse effects (itch and blushing), is relatively inexpensive and can easily be incorporated into clinical practice [35]. Therefore, it would be valuable to establish the effect of multiple sessions of ESS in conjunction with motor training in the restoration of upper limb functioning in the acute stroke phase.

The purpose of the present trial is to investigate the effect of multiple sessions of ESS treatment accompanied by motor training on the recovery of the affected upper limb following stroke. The ESS treatment is initiated in the acute stroke phase and each ESS session is immediately followed by motor training of the paretic upper limb. Specifically, we wish to address the following:

(1)

Does ESS treatment: (a) reduce motor and sensory impairments, (b) improve hand dexterity and (c) reduce disability at the end of the intervention period (short-term effect)?

(2)

Are the changes that can be observed at the end of the intervention period still present or improved at 6 months post stroke (long-term effect)?

Methods: Forty-one stroke patients received low-frequency rTMS over the contralesional hemisphere according to a standard protocol, in addition to conventional physical and occupational therapy. The rTMS-treated patients were divided into two groups according to their responsiveness to rTMS measured by the self-care score of the Korean version of Modified Barthel Index (K-MBI): responded group (n=19) and non-responded group (n=22). Forty-one age-matched stroke patients who had not received rTMS served as controls. Neurological, cognitive and functional assessments were performed before rTMS and 4 weeks after rTMS treatment.

Results: Among the rTMS-treated patients, the responded group was significantly younger than the non-responded group (51.6±10.5 years and 65.5±13.7 years, respectively; p=0.001). Four weeks after rTMS, the National Institutes of Health Stroke Scale, the Brunnstrom recovery stage and upper extremity muscle power scores were significantly more improved in the responded group than in the control group. Besides the self-care score, the mobility score of the K-MBI was also more improved in the responded group than in the non-responded group or controls.

Conclusion: Age is the most obvious factor determining upper extremity functional responsiveness to low-frequency rTMS in stroke patients.

…Task-oriented therapy is important. It makes intuitive sense that the best way to relearn a given task is to train specifically for that task. In animals, functional reorganization is greater for tasks that are meaningful to the animal. Repetition alone, without usefulness or meaning in terms of function, is not enough to produce increased motor cortical representations. In humans, less intense but task-specific training regimens with the more affected limb can produce cortical reorganization and associated, meaningful functional improvements…

Background. Although most mirror therapy studies have shown improved motor performance in stroke patients, the optimal mirror training protocol still remains unclear. Objective. To study the relative contribution of a mirror in training a reaching task and of unilateral and bimanual training with a mirror. Methods. A total of 93 stroke patients at least 6 months poststroke were instructed to perform a reaching task as fast and as fluently as possible. They performed 70 practice trials after being randomly allocated to 1 of 5 experimental groups: training with (1) the paretic arm with direct view (Paretic-No Mirror), (2) the nonparetic arm with direct view (Nonparetic-No Mirror), (3) the nonparetic arm with mirror reflection (Nonparetic Mirror), (4) both sides and with a nontransparent screen preventing visual control of paretic side (Bilateral-Screen), and (5) both sides with mirror reflection of the nonparetic arm (Bilateral-Mirror). As baseline and follow-up, patients performed 6 trials using only their paretic side. Primary outcome measure was the movement time. Results. We found the largest intervention effect in the Paretic-No Mirror condition. However, the Nonparetic-Mirror condition was not significantly different from the Paretic-No Mirror condition, while the Unaffected-No Mirror condition had significantly less improvement than the Paretic-No Mirror condition. In addition, movement time improved significantly less in the bimanual conditions and there was no difference between both bimanual conditions or between both mirror conditions. Conclusion. The present study confirms that using a mirror reflection can facilitate motor learning. In this task, bimanual movement using mirror training was less effective than unilateral training.